The 5'-untranslated region of the N-methyl-D-aspartate receptor NR2A subunit controls efficiency of translation

The N-methyl-D-aspartate (NMDA) receptor plays a central role in such phenomena as long term potentiation and excitotoxicity. This importance in defining both function and viability suggests that neurons must carefully control their expression of NMDA receptors, Whereas the NR1 subunit of the NMDA receptor is ubiquitously transcribed throughout the brain, transcription of NR2 subunits is spatially and temporally controlled, Since heteromeric assembly of both subunits is required for efficient functional expression, post-transcriptional modification of either subunit would affect NMDA receptor activity. Here it is demonstrated that the 5'-untranslated region (5'-UTR) of the NR2A subunit severely restricts its protein translation in both Xenopus oocytes and in an in vitro translation system. Mutational analysis of the 5'-UTR implicates secondary structure as the major translational impediment, while the five alternate start codons play minor roles, An important biological role for the 5'-UTR of NR2A is further suggested by the unusually high level of sequence conservation between species. In contrast, the 5'-UTR of NR1 does not inhibit translation and is not conserved. Taken together, these findings suggest a mechanism for modulation of NMDA receptor activity through the control of translational efficiency of a single subunit.